Acquired human immunodeficiency syndrome (hereinafter "AIDS") has been characterized by a depletion of CD4.sup.+ lymphocytes. As a consequence, T-cell mediated immunity is impaired in AIDS patients, resulting in the occurrence of severe opportunistic infections and unusual neoplasms.
AIDS results from the infection of T lymphocytes and other immune cells with a collection of closely related retroviruses (LAV, HTLV-III, HIV or ARV). The range of infectivity of these agents is generally restricted to cells expressing the CD4 glycoprotein on their surface. Thus,the CD4 glycoprotein is believed to serve not only as a receptor for molecules on the surface of target cells, but also as a receptor for retroviral infection.
A variety of compounds have been shown to be able to block the binding of retroviruses, such as HIV, to its cellular receptor, CD4. CD4 is the general terminology for the human CD4 receptor and its counterparts in other mammalian cells. These compounds include soluble human CD4 (Smith et al., Science, 238:1704-1707 (1987)); and synthetic fragments of human CD4 (Lifson et al., Science, 241:712-716 (1988)). Other known anti-retroviral compounds include dextran sulfate (Ito et al., Antivir. Res., 7:361-367 (1987)).
In addition, the following compounds having sulfo moieties have been reported to be effective inhibitors of several significant steps in the HIV replication cycle:
(a) Evans Blue (EB) has been reported to be an inhibitor of the interaction of HIV rgp120 with CD4 cells (Balzarini et al., Biochem. Biophys. Res. Commun., 136:64-71 (1986)); PA1 (b) Suramin and Direct Yellow 50 have been reported to be inhibitors of reverse transcriptase (Balzarini et al., Int. J. Cancer, 37:451 (1986)); and PA1 (c) bis-Naphthalenedisulfonic acid (Mohan et al., Life Science, 47:993 (1990); and Tan et al., J. Med. Chem., 35:4846 (1992)), and Fuchsin Acid (Baba et al., Biochem. Biophys. Res. Commun., 155:1404 (1988)) have been reported to be inhibitors of syncytium formation. PA1 provided that at least one of R.sup.11 to R.sup.17 is hydroxyl or amino group, at least one of R.sup.21 to R.sup.27 is hydroxyl or amino group, at least one of R.sup.11 to R.sup.17 is sulfo group, and at least one of R.sup.21 to R.sup.27 is sulfo group; PA1 A and B are individually selected from the group consisting of hydrogen atom, alkyl (C.sub.1 -C.sub.4) groups, alkoxy (C.sub.1 -C.sub.4) groups, and halogen atoms. PA1 provided that at least one of R.sup.21 to R.sup.27 is hydroxyl or amino group, and at least one of R.sup.21 to R.sup.27 is sulfo group; PA1 A and B are individually selected from the group consisting of hydrogen atom, alkyl (C.sub.1 -C.sub.4) groups, alkoxy (C.sub.1 -C.sub.4) groups, and halogen atoms; PA1 R.sup.1 is selected from the group consisting of substituted or unsubstituted alkyl (C.sub.1 -C.sub.12) substituted or unsubstituted aryl (C.sub.6 -C.sub.12), and substituted or unsubstituted heteroaryl (C.sub.1 -C.sub.12) group, Y represents --NH--, --CH.sub.2 --, or --OCH.sub.2 --; and n is 0 or 1. PA1 A and B are individually selected from the group consisting of hydrogen atom, alkyl (C.sub.1 -C.sub.4) group, alkoxy (C.sub.1 -C.sub.4) group, and halogen atom; Y represents --NH--, --CH.sub.2 --, or --OCH.sub.2 --; and n is 0 or 1.
However, most of the anti-retroviral compounds that have been heretofore described in the art cannot be administered for a prolonged period of time because of their toxicity (see U.S. Pat. No. 5,153,181). In addition, they do not have sufficient efficacy because of their weak retroviral inhibitory activity.
All U.S. patents and publications referred to herein are hereby incorporated by reference.